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Thromb Haemost 2024; 124(01): 020-031
DOI: 10.1055/s-0043-1772697
Coagulation and Fibrinolysis

Dose-Related Effectiveness of Andexanet Alfa for Reversal of Apixaban Anticoagulation in a Porcine Polytrauma Model

Farahnaz Rayatdoost 
1   Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
,
Till Braunschweig
2   Department of Pathology, RWTH Aachen University Hospital, Aachen, Germany
,
Herbert Schöchl
3   Department of Anaesthesiology and Intensive Care Medicine, AUVA Trauma Centre Salzburg, Academic Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria
,
Rolf Rossaint
1   Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
,
Oliver Grottke
1   Department of Anaesthesiology, RWTH Aachen University Hospital, Aachen, Germany
› Author Affiliations Funding Portola, San Francisco, United States, supported this work. The study sponsor had no role in the collection or interpretation of data. Medical writing and editorial support were funded by Alexion, AstraZeneca Rare Disease.
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Abstract

Background Andexanet alfa (andexanet) is a reversal agent for use in patients with life-threatening or uncontrolled bleeding treated with oral factor Xa (FXa) inhibitors. There are limited data on the dose–response relationship of andexanet and FXa inhibitor-related bleeding.

Objective The aim of this study was to assess the dose-related effectiveness of andexanet in reducing blood loss, improving survival, and reversing apixaban anticoagulation in a porcine polytrauma model.

Methods Apixaban was given orally to 40 male pigs for 3 days at a dose of 20 mg/d. On day 3, following bilateral femur fractures and blunt liver injury, animals (n = 8/group) received andexanet (250-mg bolus, 250-mg bolus + 300-mg 2-hour infusion, 500-mg bolus, or 500-mg bolus + 600-mg 2-hour infusion) or vehicle (control). Total blood loss was the primary endpoint. Coagulation parameters were assessed for 300 minutes or until death. Data were analyzed with a mixed-model analysis of variance.

Results Administration of 250-mg bolus + 300-mg infusion, andexanet 500-mg bolus, and 500-mg bolus + 600-mg infusion significantly decreased total blood loss by 37, 58, and 61%, respectively (all p < 0.0001), with 100% survival. Andexanet 250-mg bolus was ineffective in reducing total blood loss (6%) and mortality (63% survival) versus controls. Andexanet 500-mg bolus ± infusion neutralized anti-FXa activity to less than 50 ng/mL. Andexanet neutralization of thrombin generation and thromboelastometry parameters was dose and infusion time dependent.

Conclusion In a porcine polytrauma model with major bleeding on apixaban, andexanet dose dependently decreased anti-FXa activity. Lower anti-FXa levels (<50 ng/mL) with andexanet 500-mg bolus ± infusion were correlated with 60% less blood loss and 100% survival versus controls.

Keywords

anticoagulants - andexanet alfa - antidote - apixaban - polytrauma

Supplementary Material



Publication History

Received: 14 February 2023

Accepted: 20 July 2023

Article published online:
21 August 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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